Not applicable.
Not applicable.
This invention relates to administration of heparin for treating patients in need of anticoagulation therapy. More particularly, this invention relates to formulations of heparin that enhance absorption of heparin through mucosal tissues.
Heparin is widely use as one of the most potent anticoagulants for the treatment and prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE). P. S. Damus et al., Heparin-A Generalized View of its Anticoagulant Action, 246 Nature 355-356 (1973); L. Jin et al., The Anticoagulant Activation of Antithrombin by Heparin, 94 Proc. Nat""l Acad. Sci. USA 14683-14688 (1997). Heparin treatment is limited to hospitalized patients since heparin is given only by injection. R. D. Rosenberg, Biochemistry and Pharmacology of Low Molecular Weight Heparin, 34 Semin. Hematol. 2-8 (1997); G. F. Pineo and R. D. Hull, Unfractionated and Low Molecular-weight Heparin, 82 Curr. Concepts Thromb. 587-599 (1998). Patients are usually switched from intravenous or subcutaneous heparin to oral warfarin upon hospital discharge. Warfarin, however, has a slow onset and is subject to a high possibility of drug-to-drug interactions. There has been a long-felt need for compositions and methods for oral delivery of heparin for the treatment of patients who are at high risk of DVT or PE.
It is known that heparin is not absorbed in the GI tract because of its size and its highly negative charge. L. B. Jaques, Heparins: Anionic Polyelectrolyte Drugs, 31 Pharmacology Rev. 100-166 (1980). The hydrophilic properties of heparin make it difficult to penetrate epithelial cells because of low permeability and repulsion forces of the polar head group of the epithelial membrane. D. A. Norris et al., The Effect of Physical Barriers and Properties on the Oral Absorption of Particulates, 34 Advanced Drug Delivery Reviews 135-154 (1998). While administration of heparin as an aerosol or mixed with lipophilic agents or membrane enhancer agents did not result in detectable plasma heparin levels, A. Dalpozzo et al., New Heparin Complexes Active by Intestinal Absorption. I. Multiple Ion Pairs with Basic Organic Compounds, 56 Thromb. Res. 119-124 (1989), recently, N-[8-(2-hydroxybenzoyl)amino] caprylate (SNAC) was developed as a potent promoter of heparin absorption from the GI tract. R. A. Baughman et al., Oral Delivery of Anticoagulant Doses of Heparin: A Randomized, Double-blind, Controlled Study in Humans, 98 Circulation 1610-1615 (1998).
New heparin derivatives by coupling heparin with hydrophobic agents have been synthesized to increase the hydrophobicity of heparin. Y. Lee, S. H. Kim and Y. Byun, Oral Delivery of New Heparin Derivatives in Rats, 17 Pharm. Res. 1259-1264 (2000); Y. Lee, H. T. Moon and Y. Byun, Preparation of Slightly Hydrophobic Heparin Derivatives Which Can Be Used for Solvent Casting in Polymeric Formulation, 92 Thromb. Res. 149-156 (1998); U.S. patent application Ser. No. 09/300,173, now U.S. Pat. No. 6,245,753. Among those heparin derivatives, a conjugate of heparin and deoxycholic acid (DOCA) demonstrated the highest absorption in the GI tract. Two possibilities were proposed to explain these results: (1) the increased hydrophobicity of heparin due to conjugation with a hydrophobic compound, and (2) the interaction between the coupled DOCA and bile receptors in the ileum.
In view of the foregoing, it will be appreciated that providing formulations that enhance the absorption of heparin through mucosal tissues would be a significant advancement in the art.
It is an advantage of the present invention to provide formulations for enhancing the absorption of heparin through mucosal tissues.
It is also an advantage of the invention to provide formulations for enhancing absorption of heparin through the gastrointestinal mucosa after oral administration.
It is another advantage of the invention to provide methods for administering heparin for enhancing the absorption of heparin through mucosal tissues.
These and other advantages can be addressed by providing a method for making a composition for obtaining enhanced mucosal absorption of heparin comprising:
(a) dissolving an amphiphilic heparin derivative comprising heparin covalently bonded to a hydrophobic agent selected from the group consisting of bile acids, sterols, alkanoic acids, and mixtures thereof in a water phase;
(b) dispersing the water phase containing the dissolved amphiphilic heparin derivative in an organic phase such that an emulsion is formed; and
(c) drying the emulsion to result in the composition.
Illustratively, the heparin is a member selected from the group consisting of low molecular weight heparin, high molecular weight heparin, heparin fragments, recombinant heparin, heparin analogs, polysaccharides containing heparin activity, and mixtures thereof.
Another illustrative embodiment of the invention comprises a method for making a composition for obtaining enhanced mucosal absorption of heparin comprising dispersing an amphiphilic heparin derivative comprising heparin covalently bonded to a hydrophobic agent selected from the group consisting of bile acids, sterols, alkanoic acids, and mixtures thereof in an oil phase.
Another illustrative embodiment of the invention comprises a method for making a composition for obtaining enhanced mucosal absorption of heparin comprising:
(a) dissolving an amphiphilic heparin derivative comprising heparin covalently bonded to a hydrophobic agent selected from the group consisting of bile acids, sterols, alkanoic acids, and mixtures thereof in water or a water/organic co-solvent;
(b) dispersing the water or water/organic co-solvent containing the dissolved amphiphilic heparin derivative in an oil phase; and
(c) evaporating the water or water/organic co-solvent, resulting in the amphiphilic heparin derivative dispersed in the oil phase.
Still another illustrative embodiment of the invention comprises a method for making a composition for obtaining enhanced mucosal absorption of heparin comprising:
(a) dissolving an amphiphilic heparin derivative comprising heparin covalently bonded to a hydrophobic agent selected from the group consisting of bile acids, sterols, alkanoic acids, and mixtures thereof in a pharmaceutically acceptable aqueous solvent such that the amphiphilic heparin derivative forms nanoparticles in the pharmaceutically acceptable aqueous solvent; and
(b) mixing a pharmaceutically acceptable surfactant with the nanoparticles in the pharmaceutically acceptable aqueous solvent and then disrupting the nanoparticles such that the pharmaceutically acceptable surfactant interacts with the heparin and the hydrophobic agent, thereby exposing at least some of the hydrophobic agent on the outside of the nanoparticles.
Illustrative pharmaceutically acceptable surfactants including members selected from the group consisting of anionic surfactants, cationic surfactants, amphoteric surfactants, anionic surfactants, amphiphilic surfactants, hydrophobic surfactants, and mixtures thereof, and the like.
Still another illustrative embodiment of the invention comprises a composition comprising a plurality of an amphiphilic heparin derivative comprising heparin covalently bonded to a hydrophobic agent selected from the group consisting of bile acids, sterols, alkanoic acids, and mixtures thereof, wherein the plurality of the amphiphilic heparin derivative is configured as a nanoparticle having an outer surface such that at least some of the hydrophobic agents are exposed on the outer surface.
Yet another illustrative embodiment of the invention comprises a dosage form comprising a mixture of:
(a) an effective amount of a composition comprising a plurality of an amphiphilic heparin derivative comprising heparin covalently bonded to a hydrophobic agent selected from the group consisting of bile acids, sterols, alkanoic acids, and mixtures thereof, wherein the plurality of the amphiphilic heparin derivative is configured as a nanoparticle having an outer surface such that at least some of the hydrophobic agents are exposed on the outer surface; and
(b) a pharmaceutically acceptable carrier.
Another illustrative embodiment of the invention comprises a method for treating a patient in need of anticoagulation therapy comprising administering an effective amount of a composition comprising a plurality of an amphiphilic heparin derivative comprising heparin covalently bonded to a hydrophobic agent selected from the group consisting of bile acids, sterols, alkanoic acids, and mixtures thereof, wherein the plurality of the amphiphilic heparin derivative is configured as a nanoparticle having an outer surface such that at least some of the hydrophobic agents are exposed on the outer surface.